The enantioselective epoxidation of prochiral alkenes is a valuable methodology, which enables two stereogenic centres to be created in a single synthetic operation. Established methods tend to be limited to specific classes of substrate. The best known is the titanium tartrate-catalysed epoxidation of allylic alcohols, which was first reported by Sharpless as a stoichiometric method, in Katsuki et al, J. Am. Chem. Soc. (190) 102:5974, and later adapted into a catalytic variant; see Gao et al, J. Am. Chem. Soc (1987) 109:5765.
More recently, epoxidations employing chiral (salen)Mn(III) catalysts have been applied to a variety of alkene substrates, both unfunctionalised and functionalised; see Jacobsen, Chapter 4.2 in Catalytic Asymmetric synthesis, ed. I. Ojima (1993) VCH, New York.
Although both these known processes are proven as generic methodologies for laboratory-scale synthesis, reliance on metal-based catalysts and reagents means that operation on a large scale can be disadvantageous in terms of cost, work-up procedure and effluent disposal.
A third and potentially more economical methodology is the use of metal-free synthetic polypeptides such as poly-L-leucine as catalysts for the asymmetric epoxidation of prochiral .alpha.,.beta.-unsaturated ketones of the general formula EQU R.sup.1 R.sup.2 C.dbd.CR.sup.3 --CO--X (II)
to give the corresponding optically-enriched epoxides ##STR2##
This process was first reported by Julia et al, Angew. Chem. Int. Ed. Engl. (1980) 19:929. However, it is reported that high enantioselectivities are confined to trans-chalcone derivatives; see Julia et al, J. Chem. Soc., Perkin Trans. 1 (1982) 1317; Colonna et al, Tetrahedron (1983) 39:1635; Banfi et al, Tetrahedron (1984) 40:5297; Baures et al, Tetrahedron Lett. (1990) 31;6501; and Itsuno et al, J. org. Chem. (1990) 55:5047, Thus, this reaction has been considered to be of restricted scope in organic synthesis.
Optically-enriched epoxides are especially suited to nucleophilic ring-opening reactions to give, in stereocontrolled fashion, products bearing heteroatom functionality on adjacent chiral centres. In this respect, (2R,3S)-syn-3-phenylisoserine synthons are reported by Boa et al, Contemporary Organic Synthesis (1994) 1:47, and references therein. Several methods proceed via trans- or cis-phenylglycidate intermediates, prepared by enantioselective oxidation (epoxidation and dihydroxylation) of styrene derivatives; see Greene, J. Org. Chem. (1990) 55:1957; Jacobsen, J. Org. Chem. (1992) 57:4320; and Sharpless, J. Org. Chem. (1994) 59:5105. Although this is an effective overall strategy, provision of enantiopure phenylglycidates relies on the metal-based epoxidation methodologies described above, and aspects of the downstream chemistry are not well suited to operation on a large scale.
Compounds of formula I are known in racemic form. For example, compounds wherein R.sup.1 is phenyl, R.sup.2 and R.sup.3 are each H, and X is t-butyl or cyclopropyl, are disclosed in EP-A-0336841 and WO-A-0113066, and by Matano, J. Chem. Soc. Perkin Trans. I (1994) 2703, Meth-Cohn, ib. 1517, and Treves, JACS (1967) 89:6257. The nature of the functional groups makes such compounds difficult to separate into constituent enantiomers, by conventional resolution techniques.
An optically-enriched epoxide of formula I (R.sup.1 =CF.sub.3, R.sup.2 =R.sup.3 =H, X=t-butyl) is reported by Lin et al, J. Fluorine Chem. (1989) 44:113-120. Its synthesis is from optically-enriched 1,1,1-trifluoro-2-hydroxy-5,5-dimathylhexan-4-one, using lithium diisopropylamide. This is not a commercial process.
Corey et al, Tetrahedron Lett. (1991) 32:2857, report the t-butyl glycidate 5 (see Scheme 1) as the product of a chiral Darzens reaction between t-butyl bromoacetate and benzaldehyde.